Fight Aging!

Many bat species are extremely long-lived for their size, rivaling naked mole rats when it comes to a comparison with shorter-lived and similarly sized mammals. One hypothesis is that the very high metabolic demands of flight forced bats to evolve highly efficient defenses against metabolic stress, and particularly stresses generated by mitochondrial activity. Other factors have come to light, however, related to bat resilience to viral infection, triggers of chronic inflammation, and DNA damage. Bats exhibit far greater control over chronic inflammation than other mammals, for example, and researchers have experimented with moving some of the relevant biology into mice to reduce their age-related inflammation.

Today's open access paper grows from the seed of an interesting idea: can we categorize the biology of bat longevity in ways that can then be applied usefully to thinking about variation in human longevity? What does that categorization look like, and what insights emerge from it? Unfortunately the lead author is primarily involved in dietary research, and so this interesting idea, once established and explored, thereafter collapses into dietary recommendations rather than any more useful exploration of the possibilities of drug development and applied biotechnology. Departmental affiliation in academia comes with an intellectual tax that must be paid, in terms of fitting one's interesting ideas into what the department ostensibly does. Still, there something here worthy of greater consideration.

Bat-Inspired Longevity: Immune Damage Management and Nutritional Modulation for Healthy Aging

The exceptional longevity of bats challenges classical theories of inflammaging and suggests an alternative that improved resilience in responding to pathogens and cellular damage can increase longevity. Accordingly, we have developed the Core Longevity State Vector (CLSV-6) to characterize an expanded explanation for inflammaging that can be predictive of successful aging and used to develop potential strategies for successful aging. Despite high metabolic rates and persistent viral exposure, many bat species have much longer lifespans than would be predicted for mammals of their size. The increased longevity of many bat species is achieved through damage tolerance, regulated inflammasome activity, constitutive basal antiviral defenses, enhanced autophagy-mitophagy, and efficient resolution of inflammation, rather than through heightened inflammatory immunity.

The CLSV-6 is introduced as a multidimensional immunotype framework integrating six conserved mechanisms that link bat immunity to bat longevity and to human healthy aging: (1) damage tolerance, (2) autophagy-mitophagy, (3) proteostasis (management of degraded proteins), (4) basal immune readiness without activation, (5) inflammasome regulation, and (6) inflammatory resolution capacity. Together, these mechanisms enable a robust antiviral defense when needed without chronic inflammation. Notably, human centenarians converge toward this bat-like configuration. Studies suggest that centenarians often preserve more functional natural killer cells, better macrophage regulation, and improved anti-inflammatory control, with both bats and humans exhibiting reduced activation of the NLRP3 inflammasome, resulting in greater immune resilience.

Building on this framework, functional foods - including polyphenols, fermented foods, and herbal extracts - are proposed as practical strategies to shift human immunity toward bat-like, CLSV-6 immunotype by enhancing cellular quality control, regulating inflammasome activity, strengthening basal antiviral readiness, and supporting inflammatory resolution, thereby redirecting longevity strategies from immune stimulation toward damage containment and repair. This review reframes longevity as an emergent property of integrated immune damage management and provides a mechanistic roadmap for nutritional interventions to engineer healthier human aging inspired by bat immunity.

One can build a network of genes by function, by interactions between tissues, by association with specific disease, and so forth. Researchers here assemble a gene network considering associations with aging, age-related disease, and function, and attempt to derive some insight into what the shape of the network, its clusters and connectors, might say about processes of aging. They suggest that there are two broad categories of process at work here: firstly, genes that very broadly affect aging throughout the body, such as those regulating immune system or mitochondrial function, and thus tend to be associated with all age-related disease; versus secondly, genes that affect vulnerability to age-related dysfunction in one specific organ or tissue, and thus tend to be associated with a cluster of diseases associated with that organ or tissue.

Ageing-related diseases (ARDs) display diverse phenotypes yet share an age-dependent rise in incidence, suggesting mechanistic links with ageing processes. We examined whether ageing-related genes differ systematically from genes associated with multiple ARD clusters. Across 57 ARDs from UK Biobank, network analyses showed that ageing-related genes, although rarely ARD-associated, lie significantly closer to many ARDs through greater-than-chance proximity in protein-protein interaction and KEGG networks.

Our results demonstrate that the broad disease impact of highly pleiotropic genes does not require network centrality or broad expression. Rather than forming universal ageing-related cores, these genes often act within tissue-specific, weakly connected modules - a pattern consistent with previous reports that pleiotropic disease-related genes span diverse biological processes rather than collapsing onto a single functional axis.

Beyond these structural insights, our machine learning framework successfully predicted novel ageing-related gene candidates based on their connectivity to clusters of ARD-related genes. Many of these top-ranked genes belonged to conserved stress-response and signalling pathways - such as MAPK, TGF-β/SMAD, and phosphorylation cascades - reinforcing their role in systemic adaptation and maintenance during ageing.

Together, these results reveal a dual organization in the genetic architecture of ageing and multimorbidity: ageing-related genes act as cross-system integrators that maintain regulatory balance, whereas pleiotropic genes associated with specific age-related disease clusters operate as localized drivers of age-dependent disease vulnerability. Integrating these complementary perspectives provides a coherent framework for understanding how intrinsic ageing mechanisms and immune-mediated susceptibility jointly shape the landscape of human multimorbidity.

Link: https://doi.org/10.1007/s10522-026-10429-w

If one can develop a single aging clock that works in much the same way in both mice and humans, could it be used to determine which of the interventions to treat aging that have been tested in mice are more likely to work well in humans? It is clearly the case that most of the established approaches to slowing the progression of aging, largely derived from manipulation of stress response mechanisms that clean up damage and improve cell function, produce much larger increases in life span in short-lived species than in long-lived species. How will that difference manifest in an aging clock designed to work similarly in both short-lived and long-lived mammals? That is an interesting question, still awaiting an answer.

Ageing and interventions modulate health and mortality, yet the underlying molecular mechanisms of this modulation remain unclear. Here we integrate more than 11,000 transcriptomes from more than 25 tissues across 4 mammals (mouse, rat, macaque, and human) to develop accurate, interpretable rodent and multi-species biomarkers of chronological age and expected mortality, predicting lifespan-modulating interventions, time to death, chronic diseases, and rejuvenation. Ageing-related changes were conserved across species and cell types, revealing universal transcriptomic signatures of mammalian ageing and mortality, including CDKN1A and LGALS3, whose protein levels were also associated with mortality and multimorbidity in UK Biobank.

Mortality-associated features were recapitulated across in vivo and in vitro damage-accumulation models, including inflammation, replicative senescence, metabolic inhibition, and γ-irradiation, and were attenuated or reversed by cell immortalization, reprogramming, heterochronic parabiosis, and early embryogenesis. Network analysis uncovered a modular architecture of ageing- and mortality-associated hallmarks, encompassing inflammation, interferon signalling, mitochondrial function, chromatin modification, and extracellular matrix organization.

To quantify ageing of individual cellular components, we developed module-specific clocks, which revealed pathway-specific effects of interventions: chronic diseases primarily accelerated inflammatory-module ageing, whereas caloric restriction and Klotho deficiency targeted mitochondrial and metabolic modules. Transcriptomic and DNA methylation clocks showed correlated age acceleration in human blood, which was strongest for the chromatin-associated module clock, highlighting mechanistic links between molecular ageing modalities. This study reveals conserved signatures and a modular architecture of mortality regulation, providing a framework for quantifying and targeting ageing of cellular subsystems across species and tissues.

Link: https://doi.org/10.1038/s41586-026-10542-3

The gut microbiome is clearly important to health, and changes in the composition of the gut microbiome influence the progression of degenerative aging to a meaningful degree. Gut microbes of various species generate useful or harmful metabolites that interact with cells in the body. The aging of the gut microbiome is now known to reduce the supply of some useful metabolites, while increasing inflammatory interactions with the immune system. It is possible to restore a more youthful composition to the gut microbiome via a number of different approaches. Flagellin immunization encourages the immune system to more aggressively remove problematic microbial species that have grown in number with age, while fecal microbiota transplantation from a young donor to an old recipient directly resets the composition of the gut microbiome to a more youthful state.

Researchers are continuing to identify specific metabolites relevant to health and aging and the species that produce them. This will ultimately give rise to new strategies to improve health, such as supplementation of beneficial metabolites, selective removal or introduction of specific microbial species, or the tailored creation of entire new synthetic gut microbiomes that can be provided to patients. Today's open access paper is an example of the sort of research presently taking place, in which researchers identify glutamic acid as a metabolite important to oocyte quality in the aging ovaries. While provided by the gut microbiome, short term supplementation of glutamic acid does just as good a job as changes to the microbiome when it comes to restoring lost oocyte quality in old female mice.

Gut microbiota-modulated glutamic acid rejuvenates the quality of oocytes deteriorated by advanced reproductive age

The gut microbiota plays a vital role in maintaining the physiological function of host health and the pathogenesis of various diseases. However, its relationship with maternal age-associated decline in oocyte quality remains elusive. Here, we report that establishment of gut microbiota from young donors in aged mice by fecal microbiota transplantation (FMT) is an effective method to rejuvenate the quality of maternally aged oocytes. Specifically, young gut microbiota promoted the ovulation and maturation of aged oocytes, and inhibited occurrence of cytoplasm fragmentation and spindle/chromosome abnormalities, hence enhancing the oocyte quality and female fertility.

By integrating metagenome and untargeted metabolome of intestinal digesta, as well as targeted metabolome of ovaries and micro-transcriptome of oocytes, we identified that Bacteroides_caecimuris-modulated glutamic acid levels mediated the restorative effects of young gut microbiota on the aged oocytes through strengthening the mitochondria function. In addition, we demonstrated that in vivo supplementation of glutamic acid also enhanced the quality of aged oocytes, and the improvement of oocyte quality by glutamic acid was conserved across species. Altogether, our findings highlight the importance of gut microbiota in the oocyte aging and provide potential improvement strategies for age-related decline in oocyte quality and female fertility.

Once past the early stages, an atherosclerotic plaque in a blood vessel wall grows by drawing in and killing macrophage cells of the innate immune system. These cells are responsible for clearing up damage and excess lipids in blood vessel walls, but the plaque environment has become too toxic for their long term survival. Some macrophages work to resolve the issue, but most are overwhelmed, become inflammatory and eventually die. Researchers are very interested in finding possible ways to alter macrophage behavior to favor greater efforts to repair the plaque environment. One class of possible approaches involves trying to force adoption of particular set of behaviors via altering regulatory systems in the cell to override the normal reaction to the plaque environment. New options on this front arise from efforts to obtain a better understanding of which factors are in fact determining cell behavior.

Over many years, so-called macrophages - scavenger cells of the immune system - accumulate in the vessel wall. They take up fat, store it, and eventually die. What remains are cell debris and deposited fats, from which cholesterol crystals can form. These crystals destabilize plaques, promote blood clot formation, and thereby increase the risk of an acute vascular blockage. Researchers have now taken a closer look at the role played by different macrophages in atherosclerotic plaques. Not only lipid-laden macrophages but also lipid-free macrophages play a decisive role in shaping the disease process.

These lipid-free macrophages perform a dual function: on the one hand, they clear cellular debris, including DNA from dead cells, thereby limiting the formation of cholesterol crystals. On the other hand, they also attack the endothelium - the thin cell layer that lines and protects the inside of blood vessels. Inflammation, therefore, acts not only as a damaging force but also, in part, as a limiting one.

At the center of this balance is a small RNA molecule: miR-147. This microRNA is produced mainly in lipid-free macrophages. There, it helps the cells remove dead cell debris while also limiting damage to the endothelium. When miR-147 is absent, plaque formation, DNA deposits from dead cells, and cholesterol crystals all increase markedly. According to the research team, this effect is due to miR-147 suppressing the production of the protein Galectin-3 in lipid-free macrophages. When Galectin-3 is released, it not only damages endothelial cells but also disrupts the macrophages' energy supply. Without that energy, the cells clear away debris more slowly - a process that can further drive plaque formation.

Link: https://www.lmu.de/en/newsroom/news-overview/news/cardiovascular-disease-inflammation-drives-atherosclerosis-and-may-also-help-limit-it-b9e10042.html

Sepsis is a state of runaway inflammation resulting from infection, in which inflammatory signaling becomes so intense that organs fail under the stress. Crudely, one might think of initiation of sepsis as a tipping point between the normal balance of initiation and suppression of inflammation versus a runaway positive feedback loop of inflammatory signaling. Here, researchers show that the composition of the gut microbiome contributes to the risk of sepsis, and one microbial species in particular is involved in pushing individuals past the tipping point. This is one of many studies identifying specific undesirable microbial species for a near future in which highly targeted therapies can eliminate the unwanted components of the gut microbiome as needed.

Host survival during sepsis depends not only on pathogen burden but also on inflammatory thresholds calibrated by the gut microbiota. Here, we show that different survival outcomes were observed in genetically equivalent female C57BL/6 mouse populations depending on their specific gut microbiota configuration. A Muribaculaceae-enriched gut microbiota, characterized by the dominance of Sangeribacter muris KT1-3, predisposed mice to fatal sepsis caused by Acinetobacter baumannii via TLR4-dependent hyperinflammation. This lethal phenotype, reproduced by colonization with S. muris strain KT1-3, was transferable by fecal microbiota transplantation and co-housing. Notably, fixed-dose lipopolysaccharide challenge and ex vivo stimulation assays demonstrated that this configuration induces a heightened TLR4-dependent inflammatory responsiveness independent of bacterial replication.

Single-cell transcriptomics revealed that these microbiota-derived factors establish a transcriptionally pre-activated macrophage state, resulting in production of excessive pro-inflammatory cytokines upon challenge. Mechanistically, S. muris strain KT1-3 releases heat-stable and low-molecular-weight metabolites that are sufficient to potentiate systemic cytokine surges under a fixed-dose endotoxin challenge in vivo, effectively lowering the host's activation threshold for TLR4-driven signaling. Tlr4-deficient mice harboring the KT1-3-enriched susceptible microbiota survived despite persistent bacterial dissemination, demonstrating that the microbiota-TLR4 axis dictates hyperinflammatory A. baumannii-induced sepsis outcomes by modulating inflammatory magnitude rather than pathogen clearance.

Link: https://doi.org/10.1038/s41467-026-72435-3

Every cell contains hundreds of mitochondria, the descendants of ancient symbiotic bacteria that have by now evolved into components of the cell. Much of their original bacterial genome has migrated into the cell nucleus to become incorporated into nuclear DNA, leaving behind only a small remnant mitochondrial genome. The primary role of mitochondria is to supply the cell with adenosine triphosphate (ATP), a chemical energy store molecule used to power cell operations. Mitochondria interact with a range of important cellular processes beyond this, however. They continue to act much like bacteria in many other ways: they replicate, fuse together, swap component parts between one another.

The behavior of mitochondria is complex and incompletely understood, as are the contributing causes and fine details of the changes that take place in mitochondria with age. In aged cells, mitochondria exhibit reduced ATP production, greater production of oxidative molecules, altered structure, leakage of DNA fragments into the cell body where they can provoke inflammation, impaired responsiveness to quality control processes that work to remove damaged mitochondria, and so forth. Their dynamics of fusion and fission change. That all of this is important to the progression of degenerative aging is well demonstrated; numerous approaches to slowing aging in short-lived species involve improvement in mitochondrial function in aged individuals.

Still, the fact that mitochondria are so complicated has hindered efforts to produce simple therapies that can dramatically improve mitochondrial function in old humans. As things stand the best approaches remain arguably less impressive than the results of undertaking more exercise. The most plausible near future approach at this time is to transplant replacement mitochondria into old people, where the challenge is reduced to being able to harvest mitochondria from cell cultures at the enormous scale required for a medical industry based on this approach. Several companies are working on this. Meanwhile, research community efforts to better understand mitochondrial function and identify points of intervention continue. Today's open access paper is an example of the type.

FAM162A Is a Key Regulator of Mitochondrial Structure, Dynamics, and Bioenergetics, Driving Cellular Protection and Longevity

FAM162A is an inner mitochondrial protein known for its role in hypoxia-induced apoptosis. However, it is often overexpressed in cancer, where its pro-apoptotic function appears to be overridden, suggesting novel unknown roles in mitochondrial function and cell survival. Furthermore, its precise localization, topology, and orientation remain controversial. In this study, we aimed to assess the role of FAM162A in mitochondrial structure, dynamics, and bioenergetics and its impact on cellular and organismal stress resistance, while also establishing its localization, topology, and orientation.

To this end, localization, topology, and orientation were determined by protease-protection assays in COS7 cells. In vitro loss- and gain-of-function experiments assessed mitochondrial structure and function by confocal microscopy, immunoblotting, and Seahorse analysis, while a transgenic Drosophila model overexpressing human FAM162A was generated to evaluate organismal survival under normal and heat stress conditions.

We found that FAM162A localized to the inner mitochondrial membrane, predominantly within the cristae, and supported cristae ultrastructure, bioenergetics, and mitochondrial turnover, thereby enhancing oxidative metabolism, cell viability, and stress resistance. FAM162A expression was positively associated with the fusion protein OPA1 and interacted with OPA1 to regulate the proportion of long- and short-OPA1 isoforms. Transgenic Drosophila overexpressing human FAM162A exhibited increased lifespan and locomotor activity under both normal and heat stress conditions. Overall, FAM162A emerges as a key regulator of mitochondrial integrity and bioenergetics through its association with OPA1, confirming a novel role in cellular health and stress resistance.

No part of the body is truly isolated; all organs, systems, and cell populations interact with all of the others in various ways. Cells secrete and take up countless varieties of molecules and vesicles, carried throughout the body by the circulatory system to cause reactions elsewhere. Given the strong impact of reproductive success on the evolution of a species, including the characteristics of aging in that species, it perhaps shouldn't be surprising to find that germline cells get an outsized vote in the behavior of other bodily systems. In some senses, the individuals of a species are just temporary vehicles that exist to ensure the continuation of the germline, and they are shaped by the requirements of that task.

Aging is a complex biological process whose regulatory mechanisms remain incompletely understood. Accumulating evidence indicates that germ cells play pivotal roles in the systemic regulation of aging. The link between germ cells and somatic aging was first established in invertebrate models, where germ cells positively regulate the rate of organismal aging. However, whether and how this relationship operates in vertebrates has remained unresolved for nearly a quarter of a century. Recently, using the short-lived vertebrate model Nothobranchius furzeri, we demonstrated that germ cells exert sex-dependent effects on somatic aging.

In males, germ cell ablation improved healthspan and extended lifespan, accompanied by enhanced vitamin D signaling. In contrast, germ cell removal in females shortened lifespan, associated with increased IGF-1 signaling and reduced estrogen signaling. These findings suggest a vertebrate-specific mechanistic link between germ cells and somatic tissues mediated by sex-specific endocrine signaling. Such a mechanism may contribute to sexual dimorphism in reproductive strategies and potentially underlie the female longevity advantage observed across many species.

Link: https://doi.org/10.1262/jrd.2026-044

It is not surprising to find aspects of aging correlated with one another; some people have a greater burden of cell and tissue damage than others, and thus tend to be more greatly impacted in all organs and systems as a result. Equally, the failing capacity of any one organ or system can accelerate the decline of all the others. The immune system is a good example, given its importance to tissue function, and the kidney is another. Kidney function is absolutely vital for health, and impairment drags down the rest of the body. As an example of this, researchers here report on a correlation between degree of kidney aging and degree of frailty in older people.

This study aimed to investigate the association between baseline kidney function and frailty trajectories in middle-aged and older adults. Data were derived from the China Health and Retirement Longitudinal Study (2011-2018), including 5,364 participants aged ≥45 years at baseline with up to four assessment waves over approximately 7 years. Kidney function was evaluated using estimated glomerular filtration rate based on serum creatinine and cystatin C (eGFRscr-cysc). Frailty was assessed using a 30-item frailty index (0-100 scale).

At baseline, the mean frailty index was higher in participants with mildly (β=2.28) and moderately-to-severely (β=3.70) reduced kidney function compared to normal kidney function, where β represents the adjusted difference in frailty index relative to the reference group. Frailty index increased over time in all groups; in participants with normal kidney function, it rose by 0.83 points per year. The annual increase was 0.26 points greater in the mildly reduced and 0.70 points greater in the moderately-to-severely reduced group. Over approximately 7 years, predicted mean frailty index increased from 15.1 to 20.9, 17.4 to 25.0, and 18.8 to 29.5 in the normal, mildly reduced and moderately-to-severely reduced groups, respectively.

Thus middle-aged and older adults with lower kidney function exhibited higher frailty index levels at baseline and faster frailty progression over time.

Link: https://doi.org/10.1016/j.tjfa.2026.100151

You might recall that gene therapy to overexpress caveolin-1 in the brain was recently shown to reduce pathology in a mouse model of Alzheimer's disease. In today's open access paper, researchers apply the same gene therapy to a mouse model of TDP-43 pathology in the aging brain. In this model, the mice express higher than normal levels of TDP-43, and thus as they age, the animals exhibit greater levels of altered forms of TDP-43 that form aggregates and disrupt cell biochemistry in the brain as a consequence. This pathological aggregation and its consequences are particularly important in amyotrophic lateral sclerosis (ALS) and the recently named limbic-predominant age-related TDP-43 encephalopathy (LATE), but it seems likely that TDP-43 aggregation contributes in some way to all of the major named age-related neurodegenerative conditions.

Of note, the viral vector used in these studies, AAV-PHP.eB, is a relatively recently developed AAV serotype that allows for both intravenous injection and efficient transduction of cells in the brain. From a logistics and cost perspective, this is a large improvement over the need for stereotactic approaches to direct injection of the brain and intrathecal injections, and is spurring more interest in the development brain targeted gene therapies.

The mechanism by which increased caveolin-1 expression improves function in a brain undergoing neurodegenerative issues is quite interesting; it seems more suited to TDP-43 pathology than Alzheimer's pathology, as one might argue that it is actually doing something to mitigate much of the core problem of TDP-43 alteration and mislocalization, rather than only compensating for root causes by enabling greater synaptic plasticity, as seems more the case in the Alzheimer's disease models.

Systemic delivery of synapsin-promoted caveolin-1 overexpression ameliorates pathological TDP-43-induced cognitive decline and neurodegenerative changes

Transactive response DNA-binding protein 43 (TDP-43) proteinopathy is associated with frontotemporal dementia and Alzheimer's disease (AD). We previously demonstrated that synapsin-promoted caveolin-1 (SynCav1) preserves cognitive function in the mouse model of AD. This study investigated the therapeutic potential of SynCav1 in a mouse model of TDP-43 proteinopathy. AAV-PhP.eB-SynCav1 was delivered systemically to the TDP-43A315T mouse, followed by cognitive evaluation and biochemical and ultrastructural analysis of brain tissue.

Systemic AAV-PhP.eB-SynCav1 gene therapy efficiently crossed the blood-brain barrier and achieved central nervous system-wide neuroprotection. Mechanistically, pathological TDP-43 mislocalized to membrane lipid rafts (MLRs), resulting in decreased MLR-associated GluN2A expression and degenerative changes in neuronal ultrastructure. In contrast, SynCav1 delivery alleviated TDP-43 mislocalization on MLRs, stabilized MLR-associated GluN2A expression, and preserved synaptic ultrastructure. Furthermore, SynCav1 mitigated TDP-43-induced mitochondrial hyper-fragmentation and excessive mitochondrial fission signaling.

These findings establish a novel link between TDP-43 proteinopathy and MLR instability, supporting SynCav1 as a "neuron-centric" candidate for treating TDP-43-related neurodegeneration.

Macular degeneration involves the death of vital cells in the retina, leading to progressive blindness. The less common neovascular (or "wet") form of the condition involves the inappropriate growth of leaky blood vessels in the retina and underlying choroid. Existing treatments focus on trying to prevent this blood vessel growth or remove the vessels, rather than addressing underlying causes. Here, researchers make a step in the direction of those underlying causes by identifying a problem immune cell population that appears to contribute to the dysfunction and leakage of blood vessels in the eye.

Age-related macular degeneration (AMD) is the leading cause of irreversible central blindness and can result in pathological neovascularization. Using a "human-first" approach, we identify immunotherapy as a disease modifier in models of neovascular AMD. Plasma cytokine analysis in a large population cohort reveals an imbalance of lymphocytic cytokines associated with severity of AMD, leading to discovery of a skewed peripheral natural killer (NK) cell phenotype in individuals with AMD.

Peripheral NK cells are rapidly activated in neovascular AMD models, and single-cell RNA sequencing demonstrates expansion of activated cytolytic NK cells within neovascular lesions during resolution. NK cells localize to neovessels in human AMD donor eyes; however, they exhibit markers of terminal differentiation and quiescence. Adoptive transfer of pre-activated NK cells reduces neovascularization and restores barrier integrity. Our data identify a distinct, functionally altered NK cell phenotype in neovascular AMD and suggests harnessing NK cells represents an immunotherapeutic alternative for the treatment of neovascular AMD.

Link: https://doi.org/10.1016/j.xcrm.2026.102792

Researchers continue to produce new aging clocks at a fair pace. Any sufficiently complex set of biological data obtained from people of various ages can yield a clock given the use of various forms of machine learning. It is straightforward to make a new clock. Most of these will vanish into obscurity, as they will demonstrate no advantages over existing, more well studied clocks. The need is not for new clocks, but to solve the challenges inherent in the use of any clock, which is to say that it is entirely unclear as to whether a clock provides a reasonable representation of biological aging, and whether it can be trusted as an assessment of any given intervention to slow or reverse aspects of aging. The research community struggles to connect clock parameters to aging in any meaningful way that yields confidence in the ability of a clock to assess novel forms of therapy.

Amino acids are fundamental to human physiology, yet their impact on growth, development, and aging remains elusive. Here, we introduce AmiAge, a biological age predictor constructed using a Random Forest model trained on the concentrations of 18 amino acids across individuals aged 1 to 89 years. Leveraging data from 9 studies encompassing over 11,000 in-house and more than 270,000 publicly available samples with diverse demographic and genetic backgrounds,

AmiAge demonstrates robust accuracy. The deviation between AmiAge and chronological age (AmiAge Gap) correlates strongly with established aging biomarkers, disease risk, and clinical outcomes. Individuals with higher gaps exhibit increased frailty, telomere attrition, and elevated incidence of age-related diseases. To enhance clinical utility, we distilled AmiAge into an 8-amino acid model (including alanine, glutamine, glycine, histidine, leucine, phenylalanine, tyrosine, and valine). Our findings suggest that this simple, scalable amino acid clock offers a valuable complement to existing biological aging metrics, with potential applications in personalized health management and aging research.

Link: https://doi.org/10.1038/s41467-026-73371-y

In a sense, exercise is damaging. It places stress on cells, but we have evolved to react to that stress and damage with greater maintenance, repair, and a shift of cell metabolism into a more beneficial state. That a mild or short term stress results in a long term benefit is called hormesis, and it is the case for near all forms of stress. There is a point at which any form of cellular stress or metabolic disarray tips over from net benefit to net harm, a dose-response curve that looks quite similar at the high level for cold, toxins, heat, lack of nutrients, exercise, and so forth. This remains the case once you move past the source of the stress and start picking apart the biochemical changes in cell activity and cell signaling generated in reaction to that stress.

Today's open access paper looks at HMGB1 in this context of stress and hormesis relating to exercise. HMGB1 is variously regarded as devil or angel in different scientific papers, and this does tend to be the case for many of the components of a stress response. HMGB1 can produce both benefits and harms, and the dose is everything when it comes to how the balance of outcomes affects health. So HMGB1 promotes cellular senescence in bystander cells when secreted by senescent cells as a part of the senescence-associated secretory phenotype, for example. But HMGB1 also reverses some losses of DNA structure in aged cells and increases stem cell activity to accelerate regeneration. This sort of characteristic can make stress response emulation a difficult class of therapy to bring to the clinic, as optimal doses (or even whether more versus less HMGB1 is beneficial!) might vary widely from species to species and from individual to individual within a species.

High mobility group box 1: DAMPening the danger molecule in cardiovascular disease with exercise

High mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP). During cellular stress, it leaves the nucleus and moves into the extracellular space, where it modulates the development of cardiovascular diseases (CVDs), a leading global cause of age-related mortality. In preclinical models, administration of HMGB1-neutralizing antibodies increased the survival rates of lipopolysaccharide-treated mice by up to 30%, whereas treatment with recombinant HMGB1 was lethal. Furthermore, chronological aging is accompanied by a gradual increase in systemic HMGB1. Compared with young adults (18-30 years), older adults (≥70 years) have ∼ 25% higher serum HMGB1 concentrations. A longitudinal study also revealed an age-related increase in plasma HMGB1 from 3.5 ± 1.8 to 4.7 ± 1.5 ng/mL as participants aged from 24.6 ± 3.3 to 30.4 ± 3.4 years,4 suggesting that HMGB1 may reflect age-related inflammatory burden and contribute to the increased cardiovascular risk seen in older populations.

While evidence indicates that HMGB1 is associated with both the progression and severity of CVDs, it also has a paradoxically beneficial role in mitigating tissue repair. HMGB1 appears to have an important role in promoting stem cell recruitment and tissue regeneration. A role for HMGB1 in stem cell mobilization has been reported, wherein HMGB1 knockout mice exhibited impaired skeletal muscle regeneration following toxin-induced injury. In the same study, leukocyte-derived HMGB1 was required for the activation of satellite cells and vascularization in murine skeletal muscle.

Exercise training improves cardiovascular function and modulates systemic concentrations of HMGB1. Acute exercise induces the release of HMGB1 into systemic concentration, whereas long-term exercise training appears to reduce its systemic levels. This paradoxical response of HMGB1 to either short-term or chronic exercise, alongside its complex role in the pathogenesis of age-associated CVDs, makes it an intriguing subject for research. A potential explanation for this paradox may lie in HMGB1's capacity in regulating stem cell recruitment and tissue regeneration.

One of the outcomes of the past few decades of focus on the development of tissue engineering and cell therapies is an increased understanding of what can be achieved with nanomaterials, meaning any manufactured substance or structure with nanoscale features that can engage with cells in a defined way. The use of nanoscale scaffolding to emulate aspects of the extracellular matrix in order to support transplanted cells is a going concern, for example. Another line of research and development is the use of nanoparticles that are engineered to steer tissue penetration in specific directions, release cargo in response to specific stimuli, and interact with cells to alter their behavior. Here, researchers review the state of the art in the context of developing therapies for osteoarthritis, the age-related degeneration of joint tissues.

Osteoarthritis (OA) is no longer viewed as a mere "wear-and-tear" disease, but rather as a multifactorial joint failure syndrome driven by cellular senescence, metabolic dysregulation, and low-grade chronic inflammation. These pathological pillars synergistically disrupt cartilage homeostasis, subchondral bone remodeling, and synovial inflammation, collectively fueling disease progression. While conventional therapies offer only symptomatic relief, they fail to reverse or reprogram the underlying pathological microenvironment. Consequently, there is an urgent need to develop disease-modifying interventions that can simultaneously target these pathological pillars.

Here, we critically examine how nanomaterial-based platforms - leveraging tailorable surface chemistry, cartilage-penetrating dimensions, and stimuli-responsive cargo release - enable precision targeting of these interconnected mechanisms. We highlight advances in senolytic delivery for senescent cell clearance, redox-modulating nanozymes for metabolic reprogramming, and immunoregulatory strategies for macrophage repolarization, emphasizing designs that transcend passive drug delivery to actively remodel the joint microenvironment. By integrating mechanistic insights with engineering innovation, this review outlines a roadmap for next-generation disease-modifying nanomedicines that promise not merely to slow OA progression, but to restore the biological clock of the joint. We also discuss current translational barriers and propose future directions for personalized OA therapy.

Link: https://doi.org/10.2147/IJN.S584027

Allostatic load is a fairly fuzzy concept, meaning the degree of wear and tear on the body that acts degrades its ability to resist stress and function correctly. Debates over exactly how to measure allostatic load are a microcosm of the debates over exactly how to measure biological age: various scientists all using the same conceptual term to describe what turn out to be a wide range of proposed approaches to the concrete assessment of that term. The measurement is the definition at the end of the day, and so one researcher's allostatic load is not the same as that of another researcher. It remains to be seen as to whether consensus will be achieved at any point in the near future, for either biological age or allostatic load.

Chronic stress contributes to the development of cardiometabolic, malignant, and other chronic diseases through cumulative multisystem physiological dysregulation, conceptualized as allostatic load (AL). However, traditional AL relies on heterogeneous clinical biomarkers that limit reproducibility and translational utility. Here, we develop and validate ProAL50, a proteomics-based measure of AL derived from 50 circulating proteins. Using high-dimensional plasma proteomic data from the UK Biobank, we constructed ProAL50 via penalized regression and stability selection and externally validated it in the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

ProAL50 closely mirrored traditional AL in its associations with sociodemographic characteristics, lifestyle behaviors, physical and mental health, inflammation, and biological aging, supporting strong construct validity. Beyond replication, ProAL50 consistently demonstrated stronger associations with incident chronic diseases, including all cancers, type 2 diabetes, ischemic heart disease, chronic lung disease, and chronic kidney disease, and with all-cause and cause-specific mortality. Functional enrichment analyses revealed that ProAL50 proteins cluster within lipid metabolic and immune-inflammatory pathways. These findings establish ProAL50 as a scalable, biologically grounded measure of cumulative stress that not only replaces traditional AL but surpasses it in predicting disease risk and mortality, offering a novel tool for population health and translational research.

Link: https://doi.org/10.21203/rs.3.rs-8881432/v1